John McCain will turn 80 this August, and there are signs that the 4-term Senator will be in an uphill race for re-election.

The so-called "Maverick" who ran unsuccessfully for president in 2008, has tried the patience of conservsatives in Arizona for more than a decade and it appears that a combination of factors could very well lead to his defeat in November.

The Hill:

"This is a very tough challenge, probably the toughest race that he's faced since he was first elected,” Kolbe added.

McCain’s path to victory is complicated by the likelihood the GOP ticket will be headed by Donald Trump, who has an overwhelmingly negative rating among Hispanic voters, a powerful and growing electoral bloc in Arizona.

Trump has scheduled three events in Arizona Saturday with an eye on the winner-take-all presidential primary Tuesday. He will campaign with Maricopa County Sheriff Joe Arpaio, whose get-tough approach to illegal immigration has made him a national lightning rod.

Hundreds of Latino activists plan to protest Trump’s events.

If Trump, the Republican front-runner, clinches the nomination his effect on GOP candidates down ballot is hard to predict but many party strategists aren’t optimistic.

“I don’t see how Donald Trump helps any incumbent Republicans. I think he’s a drag on the ticket,” Kolbe said.

While it’s too early to tell just how serious a threat his Democratic opponent will pose, McCain’s taking it seriously. He plans to work around the state over the March recess to shore up his relations with potential voters.

Notably, he will skip the Trump rallies in Phoenix, Fountain Hills and Tucson.

McCain held town halls Friday in Mohave County in the sparsely populated northwestern corner of the state with a local electric coop and one with the chamber of commerce in Bullhead City.

Next week he’ll travel to the White Mountains in the west to hold several events with fellow Sen.Jeff Flake (R-Ariz.), whose family is from the area.

The following week he’ll travel through Phoenix, Tucson, Sierra Vista and Prescott, with several other stops along the way.

“It will be a tough race. I think it is very hard to predict this year because of all of the unique elements of this political year both on the Democratic and particularly the Republican side,” said former Sen. Jon Kyl (R-Ariz.).

“That said, I don’t know that I’ve ever seen Sen. McCain more energetic and engaged in a campaign effort than he is this time. He understands it’s a very unpredictable year. He has seen what’s happened to other candidates who have not taken their re-election seriously,” he added.

While McCain may demonstrate weakness as a general election candidate, no Republican stepped forward to challenge him as JD Hayworth did in 2010. That year, he beat Hayworth by 20 points after spending a whopping $21 million in the primary. 

McCain's moderate image may not work for him this time around. Voters appear disinterested in a politician's position on the issues and care more about what a candidate is going to do to change Washington. It's a hard case for McCain to make that he is the messenger of change when he is known far and wide as one of the most influential Washington insiders in the Senate.

And despite his advocacy for Obama's immigration reform, Hispanics are probably in no mood to do him any favors. If Donald Trump is at the top of the ticket, few Hispanic voters are likely to vote Republican under any circumstances. This would be a crippling blow to McCain, who has always counted on a significant share of Hispanic voters to win statewide. 

Ann Kirkpatrick is not the strongest Democrat McCain has faced in his career. But she man benefit from a perfect storm of conditions that would take down a key Republican Senator and make a Democratic takeover of the upper body more likely.